Reversible female contraceptives: historical, current, and future perspectives†.

Contraception is a practice with extensive and complicated social and scientific histories. From cycle tracking, to the very first prescription contraceptive pill, to now having over-the-counter contraceptives on demand, family planning is an aspect of healthcare that has undergone and will continue to undergo several transformations through time. This review provides a comprehensive overview of current reversible hormonal and non-hormonal birth control methods as well as their mechanism of action, safety, and effectiveness specifically for individuals who can become pregnant. Additionally, we discuss the latest Food and Drug Administration (FDA)-approved hormonal method containing estetrol and drospirenone that has not yet been used worldwide as well as the first FDA-approved hormonal over-the-counter progestin-only pills. We also review available data on novel hormonal delivery through microchip, microneedle, and the latest FDA-approved non-hormonal methods such as vaginal pH regulators. Finally, this review will assist in advancing female contraceptive method development by underlining constructive directions for future pursuits. Information was gathered from the NCBI and Google Scholars databases using English and included publications from 1900 to present. Search terms included contraceptive names as well as efficacy, safety, and mechanism of action. In summary, we suggest that investigators consider the side effects and acceptability together with the efficacy of contraceptive candidate towards their development.

Periostin's role in uterine leiomyoma development: a mini-review on the potential periostin poses as a pharmacological intervention for uterine leiomyoma.

Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-ß, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-ß-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.

MIG-6 Is Critical for Progesterone Responsiveness in Human Complex Atypical Hyperplasia and Early-Stage Endometrial Cancer.

Women with complex atypical hyperplasia (CAH) or early-stage endometrioid endometrial cancer (EEC) are candidates for fertility preservation. The most common approach is progesterone (P4) therapy and deferral of hysterectomy until after completion of childbearing. However, P4 therapy response rates vary, and molecular mechanisms behind P4 resistance are poorly understood. One potential molecular cause of P4 resistance is a loss or attenuation of PGR expression. Mitogen-inducible gene 6 (MIG-6) is critical for P4 responsiveness. MIG-6 protein expression in the endometrial epithelial and stromal cells from women with CAH and EEC was significantly lower compared to women without CAH or EEC. The P4-responsive women (10/15) exhibited an increase of MIG-6 expression in epithelial and stromal cells compared to P4-resistant women (5/15). In addition, immunohistochemical analysis for PGR results showed that stromal PGR levels are significantly higher in P4-responsive women compared to P4-resistant women, whereas epithelial PGR expression was not different. A reverse correlation of MIG-6 and pAKT levels was observed in early-stage EEC patients. Studies strongly suggest that loss of MIG-6 and PGR and activation of pAKT lead to P4 resistance in CAH and EEC. These results will help to elucidate the molecular mechanism leading to P4 resistance in CAH and EEC.

Robot-assisted Sentinel Lymph Node Mapping and Inguinal Lymph Node Dissection Using Near-infrared Fluorescence in Vulvar Cancer.

The surgical treatment of vulvar cancer has undergone many changes over the last century. The morbidity of open inguinal incisions prompts the search for a minimally invasive approach to lymph node dissection. This study reports the outcomes of 4 patients with vulvar cancer undergoing robotic sentinel lymph node (SLN) mapping and lymph node (LN) dissection with near-infrared fluorescence. From 2015 to 2017, 3 patients with squamous cell carcinoma of the vulva underwent robot-assisted SLN mapping and inguinal LN dissection. One patient with a vulvar melanoma had robotic bilateral SLN mapping only. The da Vinci Xi System with Firefly technology (Intuitive Surgical, Sunnyvale, CA) and indocyanine green radiotracer was used in all cases. Eight groins underwent robot-assisted SLN mapping, 6 of which underwent inguinal LN dissection. The average operating time was 234 minutes with vulvectomy. The mean blood loss was 124 mL. The operative time decreased, and the lymph node yield increased with each case. There were no wound separations or long-term negative outcomes, such as persistent lymphedema or recurrence. This case series of robot-assisted SLN mapping and inguinal lymph node dissection shows the safety and feasibility of this new technique in vulvar cancer. It may be a valid approach to reduce short- and long-term morbidity.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

Hormonal regulation of cilia in the female reproductive tract.

This review intends to bridge the gap between our knowledge of steroid hormone regulation of motile cilia and the potential involvement of the primary cilium focusing on the female reproductive tract functions. The review emphasizes hormonal regulation of the motile and primary cilia in the oviduct and uterus. Steroid hormones including estrogen, progesterone, and testosterone act through their cognate receptors to regulate the development and biological function of the reproductive tracts. These hormones modulate motile ciliary beating and, in some cases, primary cilia function. Dysfunction of motile or primary cilia due to genetic anomalies, hormone imbalances, or loss of steroid hormone receptors impairs mammalian fertility. However, further research on hormone modulation of ciliary function, especially in the primary cilium, and its signaling cascades will provide insights into the pathogenesis of mammalian infertility and the development of contraceptives or infertility treatments targeting primary and/or motile cilia.

ERBB2 Targeting Reveals a Significant Suppression of Tumorigenesis in Murine Endometrial Cancer with Pten Mutation.

Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgrcre/+Erbb2f/fPtenf/f (Erbb2d/d Ptend/d) was developed to evaluate the effect of ERBB2 targeted therapy in endometrial cancer with PTEN deficiency. Histopathological and molecular analysis was performed for Ptend/d and Erbb2d/dPtend/d mice. Histopathological analysis revealed that Erbb2d/dPtend/d mice significantly reduced development and progression of endometrial cancer compared to Ptend/d mice. Furthermore, percentage of proliferative cells in Erbb2d/dPtend/d mice revealed anti-tumorigenic effect of Erbb2 ablation compared to Ptend/d mice. Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Ptend/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Ptend/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

ARG1 is a potential prognostic marker in metastatic and recurrent endometrial cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

Leptin Stimulates Endometriosis Development in Mouse Models.

Endometriosis is a chronic inflammatory condition in women, and obesity leads to an inflammatory condition that is directly involved in the etiology of endometriosis. However, observational studies have shown an inverse correlation between endometriosis and a low body mass index (BMI). Obesity does not protect against endometriosis, and on the contrary, an increased BMI may lead to more severe forms of the disease. To determine the effect of obesity on endometriosis, diet-induced and genetically engineered obese mouse models were integrated with endometriosis mouse models with fluorescence-tagged ectopic lesions. High-fat diet-induced obese mice revealed a significant increase in endometriosis development compared with regular-diet control mice. However, obese recipient mice with leptin deficiency and leptin receptor deficiency showed suppressed endometriosis development compared with control mice. Furthermore, donor uterine tissues with leptin deficiency and leptin receptor deficiency suppressed endometriosis development compared with control donor in control recipient mice. Importantly, we revealed that aberrant high levels of leptin concentration significantly increased endometriosis development compared with vehicle treatment group in control mice with normal body weight. Our results suggest that leptin and its receptor are critical for endometriosis development.

Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year experience.

BACKGROUND: Uterine leiomyosarcoma (LMS) is associated with high rate of recurrence after surgical resection. The role of adjuvant radiation therapy in improving survival in women with uterine LMS is unclear. METHODS: All cases of LMS treated from 1985 to 2005 at 11 regional medical centers were identified. Kaplan-Meier survival curves were constructed and compared with log-rank testing. Multivariate analysis was performed to account for the potential influence of confounding factors. RESULTS: One hundred forty-seven patients with LMS were identified. The median age of diagnosis was 51 years with the stage distribution of stage I (n = 87), II (n = 9), III (n = 25), IV (n = 25), and unknown (n = 1). One hundred forty-three underwent total abdominal hysterectomy and bilateral salpingoophorectomy. Twenty-four (17%) of these patients received adjuvant pelvic irradiation, and 63 (44%) received adjuvant and/or palliative chemotherapy. With a median follow-up of 24 months (range, 1-249 months), the median survival for the entire group was 37 months. Cox proportional hazards modeling demonstrated the presence of high tumor grade and advanced stage adversely affected survival. Although the 5-year survival for patients who received adjuvant radiotherapy was significantly higher than those who did not (70% vs 35%), this survival advantage was not sustained as the curves crossed at 90-month follow-up. Pelvic recurrence rate was lower in the radiation group (18% vs 49%; P = 0.02). CONCLUSIONS: Adjuvant radiation therapy was associated with decreased pelvic failure and a modest improvement in 5-year survival, but did not impact overall survival with extended follow-up.

Cervical neoplasia in pregnancy. Part 1: screening and management of preinvasive disease.

Cervical cancer screening is an essential component of prenatal care. The diagnosis and management of cervical intraepithelial neoplasia (CIN) during pregnancy are challenging, and sufficient information does not exist to allow for a definitive evidence-based approach. The American Society for Colposcopy and Cervical Pathology has recently published guidelines regarding the evaluation of abnormal Papanicolaou tests and the treatment of CIN in this setting. Many techniques traditionally recommended in the evaluation of abnormal cervical cytology and the treatment of CIN in the nonpregnant woman, such as colposcopy, cervical biopsy, and electrosurgical excision, can be applied to the pregnant patient with important exceptions. The vascular cervix associated with the gravid condition and the risk of premature pregnancy loss mandates deviation from existing consensus guidelines in screening for cervical cancer in pregnancy and treating associated CIN. In the present review, current guidelines regarding cervical cancer screening are reviewed, and data from studies of pregnant populations are summarized.

Cervical neoplasia in pregnancy. Part 2: current treatment of invasive disease.

Although the incidence of cervical cancer in the United States has declined sharply, many young women are diagnosed with the disease every year. Naturally, coincident pregnancies will occur in this subset of reproductively active patients. Although the treatment of cervical cancer has evolved under the drive of multicenter, randomized trials, the same level of evidence does not exist for the treatment of this malignancy in pregnancy. Treatment algorithms are therefore proposed as a series of modifications to the guidelines intended for the nonpregnant patient, taking into account the tremendous social, ethical, and emotional dilemmas specific to each trimester at presentation.

Epithelial ovarian cancer and low malignant potential (LMP) tumors associated with a lower incidence of second primary breast cancer.

OBJECTIVES: Differences in the clinical characteristics of ovarian tumors of low malignant potential (LMP) and ovarian cancer have suggested divergences in tumor biology. The aim of this population-based study was to compare the risk of a second primary breast cancer after a history of either an LMP tumor or an epithelial ovarian cancer. METHODS: Breast cancers were evaluated among 3297 women with a history of LMP tumors, and 45,986 women with a history of epithelial ovarian cancer, within the Surveillance, Epidemiology, and End Results (SEER) Program. The expected incidence of breast cancer was then determined as a function of year, age, race, and geographic location, and combined with the observed incidence to derive the standardized incidence ratio (SIR). RESULTS: Forty-one (1.2%) patients with an LMP history were diagnosed with breast cancer, where 56.8 cases were expected, for an SIR of 0.72 [95% confidence interval (CI) 0.52-0.98]. Similarly, 734 patients (1.6%) with a history of ovarian cancer were diagnosed with breast cancer, where 809 were expected, for an SIR of 0.91 (95% CI 0.84-0.98). Overall, LMP patients were younger and had a shorter time between diagnoses. LMP patients also had a significantly lower relative risk of developing second primary breast cancers. CONCLUSION: Patients with a history of having either an LMP tumor or an epithelial ovarian cancer have a less than expected risk of subsequent breast cancer. Patients with LMP tumors are at lower risk than patients with a history of ovarian cancer for the development of these second malignancies.

Cost-effectiveness of adding human papilloma virus testing to a managed care cervical cancer screening program.

OBJECTIVE: The purpose of this study was to demonstrate a methodology for auditing the impact of HCII testing on the direct cost of cervical cancer cytological screening, where the test is collected in all women screened and processed routinely in women age 30 years and older. MATERIALS AND METHODS: After a policy change to screen all patients 30 years or older with both Pap smears and high-risk human papillomavirus (HR-HPV), as well as cocollection of HR-HPV in women younger than 30 years, all cytological, HPV, and histological data pertaining to cervical screening was collected retrospectively during a 2-month period. We documented the direct costs of performing these tests and estimated the necessary compliance rate for balanced cost-effectiveness. RESULTS: During the 2-month period, 8,300 women were screened with both Pap smear and HPV cocollection. Of the 'nonnormal' cytological findings, 5% of patients showed either atypical squamous cells (3.5%) or squamous intraepithelial abnormalities (1.5%). An additional 427 (5%) patients had the finding of positive HR-HPV with normal cytology. Six of these patients opted for immediate colposcopy, 2 of which were found to have cervical intraepithelial neoplasia 2. In women age 30 years and older, 900 patients per 1,000 screened would be eligible for a 2-year screening interval based on negative cytology and negative HR-HPV. Based on the direct costs associated with this cohort, no more than 164 women could request screening at an interval shorter than 3 years for the total costs of such a program to equal that of one without HR-HPV cocollection. CONCLUSIONS: By adding HCII collection to the Pap smear for our entire screening cohort, we intended to reduce the number of tests performed, which was impacted by its age distribution. Our findings indicate that at least 736 of the 900 double-negative patients (82%) would have to be screened at no less than 3 years for such a screening paradigm to be cost-effective in managing women 30 years and older.

Clinicopathologic features of six cases of primary cervical lymphoma.

OBJECTIVE: Primary lymphoma of the uterine cervix is rare, with less than 60 cases reported. We present a series of 6 patients with cervical lymphoma and review the literature. STUDY DESIGN: Between 1988 and 2003, we identified 6 women with primary lymphoma of the uterine cervix treated at our institutions. Data for analysis were obtained from hospital charts, office records, and tumor registry files. We also reviewed 20 published reports on cervical lymphoma, providing information on 58 additional patients. RESULTS: The median age at diagnosis was 52 years (range 40-76). Three patients had an abnormal Papanicolaou test within 6 months of the diagnosis. Mean tumor size was 8.3 cm (range 3-14 cm). On the basis of the Ann Arbor system of staging where "E" denotes extranodal tumor origin, 2 patients had stage IE, 1 had stage IIIE, and 3 had stage IVE disease. The median follow-up for these 6 women was 33 months (range 12-120). Adding the 6 patients in our series to the 58 patients obtained from published reports, 43 had stage IE, 14 had stage IIE, 2 had stage IIIE, and 5 had stage IVE disease. There was no consistent pattern of treatment identified from our literature review. CONCLUSION: Primary lymphoma of the uterine cervix is a rare malignancy. Most patients present with stage IE disease. Women with localized disease typically respond to various combinations of surgery, chemotherapy, and radiotherapy. Combination chemotherapy with tailored radiotherapy appears to be the preferred treatment option in women with advanced disease.